Submissions for variant NM_000535.7(PMS2):c.705+2T>C

dbSNP: rs1784783734

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179571	SCV001344263	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-08-25	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 6 of the PMS2 gene. A functional RNA study has shown that this variant causes three aberrant splicing products, including the skipping of the entire exon 6 and two different partial exon 6 deletions (PMID: 23629955). All three aberrant mRNAs are predicted to result in in-frame protein deletions in the ATPase domain. This variant has been observed as a heterozygous variant in an individual affected with gliomatosis cerebri at age 14 (PMID: 23629955). The proband is suspected to have constitutive mismatch repair deficiency without an identified second PMS2 variant (PMID: 19250412, 23629955). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001380257	SCV001578253	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the PMS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of PMS2-related conditions (PMID: 23629955; Invitae). ClinVar contains an entry for this variant (Variation ID: 920690). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 23629955; Invitae). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001780095	SCV002018881	pathogenic	not provided	2019-05-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001179571	SCV002662356	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	The c.705+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 6 in the PMS2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. This variant was identified in a male child diagnosed with gliomatosis cerebri (14y 6m) and multiple pilomatricomas (15y) who was suspected to have constitutive mismatch repair deficiency, but no second pathogenic PMS2 variant was found (Wachter-Giner T et al. Pediatr Dermatol, 2009 Jan-Feb;26:75-8; Chmara M et al. Genes Chromosomes Cancer, 2013 Jul;52:656-64). In addition, RT-PCR performed using puromycin treated EBV transformed B-cells from the patient demonstrated three associated abnormal transcripts (Chmara M et al. Genes Chromosomes Cancer, 2013 Jul;52:656-64). Based on an internal structural analysis, all three abnormal transcripts are predicted to result in in-frame protein deletions that would substantially disrupt the structure of the PMS2 ATPase domain (Ambry internal data; Guarné A et al. EMBO J, 2001 Oct;20:5521-31). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003449589	SCV004187568	likely pathogenic	Lynch syndrome 4	2023-09-19	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.